membranes lipids and signalling Flashcards
who described the fluid mosaic model?
1972 Singer and Nicholson
what do lipids spontaneously form?
bilayers
which part protrudes into the aqueous phase?
hydrophilic head groups
what are glycerophopholipids derived from?
glycerol-3-phosphate
what are glycerophopholipids?
major class of membrane lipids
what are lipid rafts?
where the average composition of a patch of the membrane is different from the bulk composition.
contain more sphingomyelin and cholesterol
what are glycerophopholipids?
major class of membrane lipids
what are lipid rafts?
where the average composition of a patch of the membrane is different from the bulk composition.
contain more sphingomyelin and cholesterol
how many fatty acid tails do glycerophopholipids have?
2
give two examples of fat that give rise to fatty acid tails.
palmitate, stearate
why do fatty acid tail have an even number of carbons?
made by stepwise addition of the two carbon molecule acetate onto growing fatty acid chains. The acetate is presented to the reaction on the carrier molecule Coenzyme A
if a tail has no double bonds what is it called?
saturated
give examples of headgroups of glycerophopholipids.
water, ethanolamine, choline, serine, glycerol, myo-inositol
name the three types of movement possible within a membrane.
lateral diffusion, rotation, transverse diffusion (flip-flop)
how is asymmetry of the membrane produced?
translocase enzymes which can flip phospholipids across the membrane in an energy dependent fashion
what do scramblase enzymes do?
randomise the normal membrane distribution of headgroups and undo the work of the translocases
when are scramblase enzymes activated?
very special circumstances such as when a platelet is activated, when a sperm fertilises an egg, or when a cell commits suicide by apoptosis.
when are scramblase enzymes activated?
very special circumstances such as when a platelet is activated, when a sperm fertilises an egg, or when a cell commits suicide by apoptosis.
what does exposure of phosphatedylserine allow?
interaction with blood clotting factors on the surface of the platelet and this can trigger the onset of blood coagulation
how is PS involved in the apoptotic cell cycle?
eat me signals
how does a cis double bond affect the chain?
produces a kink in the chain which takes up more space and results in a more fluid membrane
what do desaturases do?
introducing double bonds into fatty acids
how many different desaturases are there?
4
why do we need a supply of alpha linolenic acid and linoleic acid in our diet?
desaturases can only desaturate in certain places
what is different about sphingolipids?
sphingosine molecule as their backbone, not glycerol
always a choline head group
1 fatty acid tail is always palmitate
what does cholesterol do in the membrane?
interaction of the rigid cholesterol ring structure with acyl chains in the membrane decreases membrane fluidity at 37oC.
what does the interaction between cholesterol and sphingomyelin cause?
generation of rafts in the membrane
Different membrane proteins prefer to be anchored inside of the rafts to those that like to be anchored outside the raft
name one specific function of the rafts?
membranes can form caveolae and invaginate, which is one way that certain viruses can be internalized into cells.
what are gangliosides?
family of membrane sphingolipids that are particularly abundant in the brain. They have sugar groups attached to the sphingosine
where are glycolipids situated in the membrane?
very hydrophilic sugar groups exposed on the outer face of the plasma membrane
how are glycolipids formed?
sugars are attached to proteins (glycoproteins) and to gangliosides in the endoplasmic reticulum
bud off the ER and then travel to the Golgi apparatus where further sugar residues are added to make the branched antenna structures
reinternalized during endocytosis and vesicles fuse with lysosomes where some of the sugar tree is trimmed back
what other structure can phospholipids form and why is this important?
The storage lipids triacylglycerols (also called triglycerides) and cholesterol esters don’t form membranes. Instead they can pack into the inside of structures with one layer of phospholipids.
what other structure can phospholipids form and why is this important?
The storage lipids triacylglycerols (also called triglycerides) and cholesterol esters don’t form membranes. Instead they can pack into the inside of structures with one layer of phospholipids.
define dementia.
describes a serious deterioration in mental functions, such as memory, language, orientation and judgement
what is the most common cause of dementia?
alzheimers
what are the clinical features of Alzheimers?
amnesia, aphasia, agnosia, apraxia, viseospacial difficulties, mood disorders
what are senile plaques?
consist mainly of the short amyloid-beta (Abeta) peptide. This peptide is derived from the larger membrane bound amyloid precursor protein (APP)
what is associated with the biological process of Alzheimers?
lipid rafts in which sphingomyelin, glycolpids, cholesterol and certain membrane proteins cluster
what does APP stand for?
amyloid precursor protein
what are the three types of membrane protein?
Integral (intrinsic) membrane protein
Lipid-linked membrane protein
Peripheral (extrinsic) membrane protein
integral membrane proteins - go.
span the membrane with single or multiple transmembrane (TM) segments
interact with fatty acid chains in hydrophobic interior of bilayer
TM regions made up predominantly of amino acids with hydrophobic side chains
can only be solubilised by disrupting the membrane with organic solvents or detergents
how many TM domains does Glycophorin A have?
1
how many TM domains does Glycophorin A have?
1
what is prenylation?
addition of hydrophobic molecules to a protein or chemical compound
facilitate attachment to cell membranes,
what is a type of prenylation?
Farnesylation is a type of prenylation, a post-translational modification of proteins by which an isoprenyl group is added to a cysteine residue
what is palmitoylation?
Palmitoylation is the covalent attachment of fatty acids, to cysteine
enhances the hydrophobicity of proteins and contributes to their membrane association
what do peripheral proteins interact with?
Do not interact with hydrophobic core of bilayer
Interact with lipid headgroups or other proteins
how can peripheral proteins be removed?
high salt solution (ionic strength)
Soluble in aqueous solution
give examples of cytoskeletal proteins.
Spectrins - form 200 nm long filaments
Ankyrin - bridges spectrin and band 3 protein
Actin - joins spectrin filaments
Band 4.1 - stabilises spectrin-actin interaction
what is the role of the cytoskeleton?
important in maintaining shape and rigidity of cell AND in restricting the lateral motion of integral membrane proteins
what is hereditary spherocytosis and elliptocytosis?
Mutations in genes encoding spectrin or ankyrin
Result in abnormally shaped erythrocytes
Degraded more rapidly by spleen
=> anaemia
how is the Abeta peptide formed?
proteolytically cleaved from the
membrane-bound amyloid precursor protein (APP)
how does taking statins reduce risk of alzheimers?
statins lower Ab production in cells
statins alter cholesterol content and hence fluidity of
membrane rafts
why do lipid rafts increase the risk of alzheimers?
processing of APP in the cholesterol-rich lipid rafts produces the toxic amyloid-beta peptide, whereas cleavage of APP in other regions of the membrane preclude the formation of amyloid-beta.
where are sugars located on the membrane?
located almost exclusively on the extracellular face of the membrane.
what are the two ways sugars can be linked to proteins?
O-linked to Ser/Thr
N-linked to Asn—X—Ser/Thr (as long as X is not Pro)
what sugars are O-linked?
often short consisting of 2-5 sugars.
what sugars are N-linked?
usually large branched structures with as many as 30-40 sugar residues
what sugars are N-linked?
usually large branched structures with as many as 30-40 sugar residues
what is the function of carbohydrates in membranes?
stability of proteins
intercellular recognition e.g. blood group antigens (ABO)
why would a pure lipid bilayer not work?
only permeable to H2O, small hydrophobic molecules and small uncharged molecules.
simple diffusion across a membrane - go (3 points)
(non-mediated transport)
small molecule, e.g. O2, CO2, urea.
-no specificity
-rate of diffusion proportional to concentration gradient
facilitated diffusion across a membrane - go (5 points)
occurs down concentration gradient
no energy required
depends on integral membrane proteins
(Carriers, permeases, channels, transporters)
proteins are specific
similar kinetics as enzymes, i.e. is saturable, inhibitable, etc.
what do ion channels allow?
Highly selective rapid and gated passage of anions and cations
what are ion channels essential for?
maintaining osmotic balance
signal transduction
nerve impulses
how is glucose transported into erythrocytes?
. The integral membrane protein the glucose transporter facilitates the movement of the glucose across the plasma membrane.
undergoes transformational change when glucose binds and returns back to normal when glucose is hrough
what are aquaporins needed for?
water channel proteins required for the bulk flow of H2O across cell membranes
what are the two ways active transport can be driven?
ion-driven or ATP-driven
give an example of an ATP driven process.
Na+/K+ ATPase
high [K+], low [Na+] in cell
Na+/K+ gradient:
controls cell volume
nerve and muscle cells electrically excitable
drives active transport of amino acids and sugars
maintained by Na+/K+ ATPase
energy released is used to pump 3 Na+ ions out of the cell and 2 K+ ions into the cell.
give an example of an ATP driven process.
Na+/K+ ATPase
high [K+], low [Na+] in cell
Na+/K+ gradient:
controls cell volume
nerve and muscle cells electrically excitable
drives active transport of amino acids and sugars
maintained by Na+/K+ ATPase
energy released is used to pump 3 Na+ ions out of the cell and 2 K+ ions into the cell.
which are the only ions which are directly coupled with ATP hydrolysis?
only Na+, K+, Ca2+ and H+ transport is directly coupled
to ATP hydrolysis
what other active process moves substrates across?
co-transport - can be symport or antiport
how does digoxin work?
inhibit the Na+/K+ ATPase,
increased concentration of Na+ inside the cell decreased Na+ gradient across the membrane
Na+ gradient required for the Na+/Ca2+ exchanger
leads to an increased concentration of Ca2+ inside the cell.
leads to enhanced strength of heart muscle contraction.
what is the basis of oral rehydration therapy?
the uptake of glucose is critically dependent on the presence of Na+ ions in the lumen of the gut and that as glucose moves into the body it alters the osmotic pressure causing water to follow
what is the basis of oral rehydration therapy?
the uptake of glucose is critically dependent on the presence of Na+ ions in the lumen of the gut and that as glucose moves into the body it alters the osmotic pressure causing water to follow
why do cells communicate with one another?
regulate their development and organisation into tissues
control their growth and division
co-ordinate their functions
what are the three ways cells communicate with one another?
remote signalling by secreted molecules
contact signalling by plasma membrane-bound molecules (Juxtacrine signalling)
contact signalling via gap junctions
what are the three phases in remote signalling?
Reception of an extracellular signal by the cell. Transduction of the signal from outside the cell to inside the cell (can often be multi-stepped).
Activation of the cellular response.
give examples of first messengers.
growth factors
neurotransmitters
hormones
what are 1st messengers synthesised and secreted by?
signalling cells
what are the 4 types of cellular signalling?
paracrine, endocrine, autocrine, neuronal
what is a hormone?
a chemical messenger released by a cell, a gland, or an organ in one part of the body, is transported in the blood and affects cells in other parts of the body.
what is a hormone?
a chemical messenger released by a cell, a gland, or an organ in one part of the body, is transported in the blood and affects cells in other parts of the body.
where are the receptors found for lipid based hormones?
inside of the cell
what are the 2 groups of hydrophilic hormone?
catecholamines, peptide hormones
what are the three groups of lipid-based hormones?
steroids, thyroid hormones, sterol hormones
how is specificity achieved in signalling?
lock and key model
what are the 4 different receptor types?
Ligand-gated ion channels
G-protein-coupled receptors (GPCRs)
Kinase-linked receptors
Nuclear receptors
characteristics of ligand-gated ion channels
Ionotropic receptors
Binding and channel opening is very fast
Involved in fast synaptic transmission
Ligand-binding site on the extracellular side
Comprise 4 or 5 heteromeric subunits surrounding central pore
characteristics of GCPRs
integral membrane protein receptors and consist of a single polypeptide, comprising 7 membrane-spanning alpha-helical regions
Metabotropic or heptahelical receptors
Couple to an intracellular effector system via a G-protein
describe GCPR signalling
Binding of a hormone causes conformational change of the receptor,
modulates the activities of downstream effector proteins modulate the levels of 2nd messenger molecules (e.g. cAMP, cGMP, IP3, DAG and Ca2+; or regulate ion channel opening
determine a cells membrane potential.
describe GCPR signalling
Binding of a hormone causes conformational change of the receptor,
modulates the activities of downstream effector proteins modulate the levels of 2nd messenger molecules (e.g. cAMP, cGMP, IP3, DAG and Ca2+; or regulate ion channel opening
determine a cells membrane potential.
what is the RA system stimulated by?
decrease in blood volume, blood Na+ or blood pressure
what are the two main enzymes in the RAS?
renin
angiotensin-converting enzyme
what type of receptor is angiotensin 2?
GPCR
what effects are mediated by AT1 receptors?
vasoconstriction
increased NA release from sympathetic nerve terminals, stimulation of proximal tubular Na+ reabsorption, aldosterone secretion from the adrenal cortex
vascular growth
what effects are mediated by AT2 receptors?
in anti-hypertrophic and anti-hypertensive effects (i.e. AT2 receptor activation opposes the effects of AT1 receptor activation).
how many trans membrane sections do kinase-linked receptors have?
1
what are kinase linked receptors dependent on?
enzymic nature of the intracellular domain
what are the two different types of kinase -linked receptor?
Catalytic receptors
receptor is itself an enzyme
e.g. insulin
Non-catalytic receptors
act through cytoplasmic tyrosine kinases
e.g. cytokines
give examples of ligands for non-catalytic receptors.
cytokines (interleukin, interferon), growth hormone and prolactin.
give example of catalytic receptors.
Tyrosine kinase receptors (activated by insulin and some growth factors),
Serine/Threonine kinase receptors (activated by transforming growth factor)
guanylate cyclase (cGMP)-linked receptors
what happens when a ligand binds to a kinase -linked receptor?
receptor dimerization occurs and they become activated
how do kinase linked receptors act?
act by indirectly regulating gene transcription (timescale: hours)
what do nuclear receptors regulate?
regulate the transcription of certain genes (timescale: hours)
what structure do nuclear receptors have?
separate ligand- and DNA-binding domains
zinc fingers are in the DNA-binding domains
how do hormones activate nuclear receptors?
diffuse across the plasma membrane and interact with intracellular receptors; located either within the cytosol
hormone-receptor complex translocates to the nucleus.
how do hormones activate nuclear receptors?
diffuse across the plasma membrane and interact with intracellular receptors; located either within the cytosol
hormone-receptor complex translocates to the nucleus.
what are the three parts of a neuron and what are there functions?
Dendrites receive information (nerve impulses)
Cell body
assimilates the information
Axon
ends at the nerve terminal
what happens when an impulse reaches the nerve terminal?
causes the synaptic vesicles to fuse with the plasma membrane and release their neurotransmitter contents by exocytosis
neurotransmitter diffuses across the synaptic cleft, binds to specific post-synaptic receptors and initiates a cellular response.
5 stages in the life cycle of a neurotransmitter
(1) Synthesis: in the nerve terminal (except for neuropeptides),
(2) Storage: in synaptic vesicles within nerve terminals, (3) Release: into the synaptic cleft from pre-synaptic vesicles by exocytosis (this is a Ca2+-dependent process) in response to an action potential,
(4) Receptor activation: diffuse across the synaptic cleft and act on post-synaptic cell
(5) Neurotransmitter inactivation: action is short lived due to enzyme metabolism and/or re-uptake
what is the role of antidepressants?
to increase monoaminergic transmission within the synaptic cleft
5 different treatments for depression.
Monoamine reuptake inhibitors
TCAs, SSRIs, SNRIs
Monoamine oxidase inhibitors (MAOIs)
Miscellaneous “atypical” antidepressants
Electroconvulsive therapy (ECT)
Mood-stabilising drugs (e.g. Lithium)
3 modes of action for antidepressant drugs.
binding to pre-synaptic nerve terminal monoamine transporters inhibiting reuptake and raising NT levels in the synaptic cleft
prevent the breakdown on monoamines within the nerve terminal; and thus ensures more monoamine NTs are available for release
non-selective antagonists at presynaptic autoreceptors (inhibits feedback loop → possible increased monoamine NT transmission).
give 3 examples of gasotransmitters.
nitric oxide (NO), carbon monoxide (CO) and hydrogen sulphide (H2S).
what type of signalling do gasotransmitters produce?
paracrine
what is the signal transduction hierarchy?
1st messenger, receptor, G-protein, effector enzyme, 2nd messenger, protein kinase, target protein, cellular response
what are the main amplification points in the hierarchy?
G-protein activation - the G-protein is activated by the receptor as long as the receptor remains in an activated state.
Effector enzyme - as these are enzymes, they will catalyse reactions without being used up.
Protein kinase - again the protein kinase is an enzyme.
how many molecules can 1 binding ligand create?
10^8
4 ways complexity is increased in signal transduction
1000+ GPCRs
500+ protein kinases
Cross-talk
Cell-type specificity
why are G proteins called G proteins?
Guanine nucleotide binding proteins
They are also enzymes (“GTPases”) that can catalyse hydrolysis of GTP to form GDP (this switches the G-protein off).
where are G proteins anchored?
anchored to the internal surface of cell membranes via lipid tails (prenylated)
what are the two major groups of G-protein?
G-proteins (receptor-associated)
heterotrimeric (a, b, g subunits)
e.g. Gas, Gai , Gaq
Small GTPases
monomeric
e.g. Ras, Rho
why are G-proteins molecular switches?
Switched “ON” by ligand binding to receptor
Switched “OFF” by intrinsic GTPase activity
what are the main groups of alpha subunit of G-protein?
Gi (“inhibitory”), Gs (“stimulatory”), Gq/11 and G12,13
what are the main groups of alpha subunit of G-protein?
Gi (“inhibitory”), Gs (“stimulatory”), Gq/11 and G12,13
what does Gi do?
inhibition cAMP
what does Gs do?
increase cAMP
what does Gq do?
increase DAG and IP3
what does G12,13 do?
activates Rho
describe the process of a ligand binding to Gs
Binding of ligand to receptor causes the G-protein to release GDP and swap it for GTP, thus switching the G-protein to the “ON” state. The GTP bound alpha subunit dissociates from the beta and gamma subunits.
The GTP-bound Gs-alpha subunit binds to and activates adenylyl cyclase which catalyses conversion of ATP to the second messenger cyclic AMP.
The GTPase activity of the Gs-alpha subunit hydrolyses GTP to GDP (with release of inorganic phosphate, Pi), thus reverting the G-protein back to the “OFF” state.
The GDP-bound alpha subunit then re-associates with the beta and gamma subunits.
Cyclic AMP is broken down to AMP by phosphodiesterases.
what is the effector enzyme for Gi and Gs?
adenylate cyclase
what is the effector enzyme for Gq?
Phospholipase C
which disease affects Gs proteins?
cholera
what is the action of the cholera toxin?
prevents GTPase activity of Gs, therefore GTP remains bound to Gs and it stays in the “ON” state.
elevated cAMP increases loss of Cl- ions through chloride channels. The resultant osmotic gradient leads to water being excreted into the intestinal lumen and hence diarrhoea and dehydration.
what is the action of the pertussis toxin?
prevents GDP/GTP exchange by Gi
protein is locked in the “off” position. This leads to it being unable to inhibit adenylate cyclase, resulting in accumulation of cyclic AMP.
increased insulin secretion and increased sensitivity to histamine
describe the process of a ligand binding to Gs
Binding of ligand to receptor causes the G-protein to release GDP and swap it for GTP, thus switching the G-protein to the “ON” state. The GTP bound alpha subunit dissociates from the beta and gamma subunits.
The GTP-bound Gs-alpha subunit binds to and activates adenylyl cyclase which catalyses conversion of ATP to the second messenger cyclic AMP.
The GTPase activity of the Gs-alpha subunit hydrolyses GTP to GDP (with release of inorganic phosphate, Pi), thus reverting the G-protein back to the “OFF” state.
The GDP-bound alpha subunit then re-associates with the beta and gamma subunits.
Cyclic AMP is broken down to AMP by phosphodiesterases.
what is the action of the pertussis toxin?
prevents GDP/GTP exchange by Gi
protein is locked in the “off” position. This leads to it being unable to inhibit adenylate cyclase, resulting in accumulation of cyclic AMP.
increased insulin secretion and increased sensitivity to histamine
define second messenger
Short-acting intracellular molecules that are rapidly formed or released as a result of receptor activation
5 common second messengers
Cyclic AMP (cAMP) Cyclic GMP (cGMP) Diacylglycerol (DAG) Inositol 1,4,5-trisphosphate (IP3) intracellular calcium (Ca2+i)
what are the actions of adenylate cyclase and guanylate cyclase opposed by?
phosphodiesterases
Some PDEs specifically break down cyclic AMP to AMP. Others break down cyclic GMP to GMP
describe the process of a ligand binding to Gq
causes receptor to associate with G protein (Gq). This stimulates displacement of GDP by GTP (switching G-protein “on”)
production of two different second messengers 1,2-diacyclycerol (DAG) and inositol 1,4,5-trisphosphate (IP3)
stimulates protein kinase C (PKC) that phosphorylates target proteins leading to cellular responses
where is intracellular calcium stored?
endoplasmic reticulum (ER) and mitochondria under normal conditions so the cytosolic concentration is low
how is calcium released from the ER?
IP3 binds to receptors in the ER membrane resulting in efflux of Ca from the ER
what are protein kinases?
Enzymes that facilitate transfer of a phosphate group from ATP to a specific amino acid residue (Ser, Thr or Tyr) on a specific protein
what are the three main groups of protein kinase?
Serine/Threonine kinases
Phosphorylate Ser and/or Thr residues
Tyrosine kinases
Phosphorylate only Tyr residues
Dual-specificity kinases
Phosphorylate Ser/Thr and Tyr residues
what action do phosphatases have?
remove phosphate groups from amino acids residues to oppose the effects of kinases and switch the switch in the opposite direction.
what are the two main groups of phosphatase?
Ser/Thr-directed phosphoprotein phosphatases (PPPs) and the Tyr-directed phosphotyrosine phosphatases (PTPs)
what are the two main ways kinases can alter protein function?
phosphorylation of a protein leading to a conformational change that directly alters the function of that particular protein
switch on/off gene transcription and hence regulate expression levels of many other proteins as a result.
what is linked to the dysregulation of kinases?
cancer development
what is linked to the dysregulation of kinases?
cancer development
what are the main functions of lipids?
Energy storage
Major components of cell membranes
Required to solubilise fat soluble vitamins
Biosynthetic precursors (e.g. steroid hormones from cholesterol)
Signalling molecules
where does cholesterol come from?
25% diet
synthesised in liver
how is cholesterol carried?
Insoluble in blood plasma, transported with a “carrier” – lipoprotein
what is the function of lipoproteins?
The principal means of lipid (triglycerides and cholesterol) transport in blood
how are lipoproteins classified?
Classified according to density & chemical properties
Share a general structure, different ratios protein:lipids
what are the 4 types of lipoprotein?
HDL, LDL, VLDL, chylomicron
where is the main source of HDLs?
blood
where is the main source of LDLs?
VLDLs
where is the main source of VLDLs?
liver
where is the main source of chylomicrons?
intsetine
which is the main cholesterol carrier?
LDL
what features are located in the external monolayer of lipoproteins?
phospholipids, cholesterol and apolipoproteins
what are located in lipoprotein cores?
Cholesterol esters and triacylglycerols
what are the main classes of apolipoprotein?
ApoA
ApoB
ApoC
ApoE
what are the characteristics of ApoA?
present in HDL, mediates efflux of cholesterol from peripheral cells and influx to the liver
what are the characteristics of ApoB?
recognises apoB/E receptors, facilitates LDL uptake
what are the characteristics of ApoC?
activator of lipoprotein lipase, transferred between lipoproteins
what are the characteristics of ApoE?
stabilises VLDL for cellular uptake, a ligand for the apoB/E (LDL) receptor. Constituent of several classes of lipoproteins
how are HDL and LDL different?
LDL has 1 band of ApoB HDL has 2 Bands OF APOA1 and ApoA2
HDL more resistant to oxidative modification
what do chylomicrons do?
made in the intestine, transport triglycerides and cholesterol in the blood
Triglycerides are hydrolysed by lipoprotein lipase to fatty acids that are taken up by target tissues and used for energy production (eg muscle) or stored (adipose tissue). Chylomicrons shrink, remnants transported back to liver.
what do VLDLs do?
transport lipids to target tissues, acted on by lipoprotein lipase to release fatty acids & taken up by target tissues . VLDL remnants remain in the blood, become LDL
what do LDLs do?
taken up by target cells by the LDL receptor, digested in the lysosome to release the cholesterol
what do HDLs do?
remove cholesterol from the tissues. HDL are synthesised in the blood and acquire their cholesterol by extracting it from cell membranes and transporting back to the liver.
what are lipoprotein receptors?
Membrane-bound receptors to enable cholesterol entry to hepatic and peripheral cells
what are lipoprotein receptors?
Membrane-bound receptors to enable cholesterol entry to hepatic and peripheral cells
what does the LDL receptor bind and what is it regulated by?
LDL receptor (apoB/E receptor), binds apoB-100 or apoE
LDL receptor gene expression is regulated by intracellular cholesterol concentration
what is different about lipoprotein A and why is it bad?
Long polypeptide chain
linked to ApoB-100
apolipoprotein(a)
Multiple “kringle” structures
(amino acids)
to implicate this lipid in increased risk of cardiovascular disease
what do high serum cholesterol levels mean?
risk for cardiovascular diseases (atherosclerosis)
A major constituent of atherosclerotic plaques is cholesterol-enriched LDL
what are the clinical manifestations of atherosclerosis?
Chest pain, palpitations, heart attack, Stroke, cerebral haemorrhage, Pain, ischaemia, ulceration & gangrene
what is the cholesterol synthetic pathway?
HMG-CoA Mevalonate IPP FPP Squalene cholesterol
what is the rate limiting step of cholesterol production?
HMG-CoA reductase conversion of HMG-CoA to mevalonate
what do statins do?
inhibit HMG-CoA reductase
what does pleiotropic mean?
Actions other than those for which the agent was specifically developed
what are FPP and GGPP?
Farnesyl pyrophosphate (FPP) Geranylgeranyl pyrophosphate (GGPP) ISOPRENOIDS
why are Ras and Rho involved in the cholesterol pathway?
Ras is farnesylated whilst Rho is geranylgeranylated
